T-98475, -Drug Synthesis Database

【结构式】

【药物名称】T-98475

【化学名称】3-(N-Benzyl-N-methylaminomethyl)-7-(2,6-difluorobenzyl)-2-[4-(isobutyramido)phenyl]-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid isopropyl ester hydrochloride

【CA登记号】192887-28-8, 199119-18-1 (free base)

【分子式】C₃₇H₃₈ClF₂N₃O₄S

【分子量】694.24691

【开发单位】Takeda (Originator)

【药理作用】ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Oncolytic Drugs, GnRH (LHRH) Antagonists

合成路线1 合成路线2

合成路线1

Aminothiophene (III) was prepared by condensation of phenylacetone (I) with ethyl cyanoacetate (II), followed by treatment with sulfur and diethylamine. Subsequent condensation of (III) with diethyl ethoxymethylenemalonate (IV) at 120 C provided the enaminomalonate (V). the partial hydrolysis of (V) with KOH in EtOH-dioxan provided monoacid (VI), which was cyclized by means of PPE to the thienopyridine (VII). Alkylation of (VII) with 2,6-difluorobenzyl chloride (VIII) and K2CO3 yielded predominantly the N-benzylated compound (IX), which was selectively nitrated at the phenyl ring to produce (X) (2). Radical bromination of the 3-methyl group of (X) gave bromomethyl compound (XI).

参考文献中间体

【1】 Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.; Hayase, Y.; Sasaki, S,; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.; Endo, S.; Onda, H.; Fujino, M.; Discovery of a novel, potent, and orally active no. J Med Chem 1998, 41, 22, 4190.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	23143	1-Phenylacetone; Methyl benzyl ketone; Benzyl methyl ketone; phenylacetone; Phenyl-2-propanone	103-79-7	C₉H₁₀O	详情	详情
(II)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(III)	23145	ethyl 2-amino-4-methyl-5-phenyl-3-thiophenecarboxylate		C₁₄H₁₅NO₂S	详情	详情
(IV)	14088	Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate	87-13-8	C₁₀H₁₆O₅	详情	详情
(V)	23147	diethyl 2-([[3-(ethoxycarbonyl)-4-methyl-5-phenyl-2-thienyl]amino]methylene)malonate		C₂₂H₂₅NO₆S	详情	详情
(VI)	23148	2-[[3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propenyl]amino]-4-methyl-5-phenyl-3-thiophenecarboxylic acid		C₂₀H₂₁NO₆S	详情	详情
(VII)	23149	ethyl 4-hydroxy-3-methyl-2-phenylthieno[2,3-b]pyridine-5-carboxylate		C₁₇H₁₅NO₃S	详情	详情
(VIII)	23150	2-(chloromethyl)-1,3-difluorobenzene	697-73-4	C₇H₅ClF₂	详情	详情
(IX)	23151	ethyl 7-(2,6-difluorobenzyl)-3-methyl-4-oxo-2-phenyl-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₂₄H₁₉F₂NO₃S	详情	详情
(X)	23152	ethyl 7-(2,6-difluorobenzyl)-3-methyl-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₂₄H₁₈F₂N₂O₅S	详情	详情
(XI)	23153	ethyl 3-(bromomethyl)-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₂₄H₁₇BrF₂N₂O₅S	详情	详情

合成路线2

Compound (XI) was condensed with methyl benzyl amine (XII) to furnish tertiary amine (XIII). The nitro group of (XIII) was then reduced with iron powder and HCl to afford amine (XIV). Subsequent acylation of (XIV) with isobutyric anhydride (XV) in the presence of Et3N produced amide (XVI). The title compound was then obtained by transesterification between (XVI) and titanium isopropoxide in isopropanol, followed by treatment with ethanolic HCl.

参考文献中间体

【1】 Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.; Hayase, Y.; Sasaki, S,; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.; Endo, S.; Onda, H.; Fujino, M.; Discovery of a novel, potent, and orally active no. J Med Chem 1998, 41, 22, 4190.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	11969	N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine	103-67-3	C₈H₁₁N	详情	详情
(XIII)	23155	ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₂H₂₇F₂N₃O₅S	详情	详情
(XIV)	23156	ethyl 2-(4-aminophenyl)-3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₂H₂₉F₂N₃O₃S	详情	详情
(XV)	22334	1-methylpropionic anhydride	97-72-3	C₈H₁₄O₃	详情	详情
(XVI)	23158	ethyl 3-[[benzyl(methyl)amino]methyl]-7-(2,6-difluorobenzyl)-2-[4-(isobutyrylamino)phenyl]-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate		C₃₆H₃₅F₂N₃O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)